During the development of atherosclerosis, monocytes are recruited to the vessel wall where they[unreadable] differentiate into macrophages and accelerate the development of this disease. Monocyte differentiation is[unreadable] associated with the up-regulation of a number of macrophage receptors, including pattern-recognition[unreadable] scavenger and toll-like receptors that are involved in innate immunity, as well as endocytotic and signaling[unreadable] receptors such as the low density lipoprotein receptor-related protein (LRP). This LDL receptor family[unreadable] member is widely expressed and plays important roles in lipoprotein metabolism, degradation of proteases,[unreadable] and in signaling pathways. During the previous funding period of this program project grant the results of our[unreadable] work revealed that LRP modulates a diverse range of physiological events. First, using oligionucleotide[unreadable] microarray data, we obtained evidence that LRP increases the gene expression of several inflammatory[unreadable] cytokines and chemokines, including MCP-1. Second, in collaboration with project 2, we discovered that[unreadable] association of active tPA with LRP in the brain leads to permeability of the blood brain barrier resulting in[unreadable] increased damage induced by ischemia during stroke. Third, in collaboration with project 3 we found that[unreadable] LRP cooperates with the integrin Mac-1 to modulate macrophage migration thereby modulating[unreadable] inflammation. The central hypothesis of this application is that LRP regulates inflammatory events in the[unreadable] vessel wall and the specific hypotheses to be tested are: 1) that LRP regulates inflammatory processes by[unreadable] modulating the functional properties of integrins and thereby affects macrophage migration, 2) that[unreadable] macrophage LRP promotes the uptake of lipoproteins in the vessel wall and contributes to the development[unreadable] of atherosclerosis, 3) that LRP functions as an important phagocytic receptor and modulates the production[unreadable] of inflammatory cytokines via a signaling mechanism involving release of LRP's ICD. These hypotheses will[unreadable] be tested in the following aims: 1) Investigate the role of LRP in a vascular injury model and identify[unreadable] mechanisms by which LRP modulates macrophage migration 2) Investigate the hypothesis that macrophage[unreadable] LRP modulates lipoprotein uptake in the vessel wall thereby promoting atherosclerosis and 3) Evaluate the[unreadable] role of LRP in phagocytosis and determine if this event triggers signaling cascades that induce production of[unreadable] inflammatory molecules.